Based on our work on the mechanism of T lymphocyte or programmed cell death or apoptosis, we have studied autoimmune diseases in two areas: 1) pathogenesis and 2) treatment. We have determined the molecular pathogenesis of one form of autoimmunity by studying a group of children that had been followed by Drs. Stephen Straus and Warren Strober in the LCI, NIAID. These children exhibit an autoimmune/lymphoproliferative syndrome (ALPS) consisting of massive nonmalignant lymphadenopathy, autoimmune phenomena and expanded populations of CD3+, CD4-, CD8- lymphocytes together with antibody-mediated autoimmune disorders. We found that several ALPS children have mutations in the apoptosis-inducing molecule Fas that cause defective Fas-mediated T lymphocyte apoptosis. Transfection studies directly demonstrated that mutant Fas proteins were not only unable to deliver a death signal, but also had a dominant negative phenotype when co-expressed with normal Fas. Family studies showed that the mutations were inherited and thus defined the molecular basis of a genetic autoimmune disorder. With regard to treatment of autoimmune diseases, we are testing tolerance due to T cell apoptosis as a new modality of immune therapy. A CRADA has been established to test whether T cell apoptosis can be predictably induced by antigen in various animal models of autoimmune disease and graft rejection. The ultimate purpose of these investigations is to advance apoptosis therapy for T cell-mediated diseases to a clinical trial. A primary goal of the CRADA at present is to establish whether the administration of myelin antigens as an antigen-specific therapy can alleviate multiple sclerosis (MS). In preparation for a clinical trial, we have accomplished several things: 1) building and testing recombinant versions of myelin antigens, 2) establishing the relevant animal models to test efficacy and dosing, 3) refining means to test for the elimination of myelin-reactive T cells in peripheral blood. In addition to MS, we have begun work on a transgenic mouse model for myasthenia gravis.